1. Field of the Invention
The present invention relates to oral peptide pharmaceuticals where the active compounds include a plurality of amino acids and at least one peptide bond in their molecular structures, and to methods of enhancing bioavailability of such peptide active compounds when administered orally.
2. Description of the Related Art
Numerous human hormones, neurotransmitters and other important biological compounds have peptides as a substantial part of their molecular structures. Many diseases respond positively to raising the level of these peptide compounds in patients. Therapeutically effective amounts of such biologically relevant peptides may be administered to patients in a variety of ways. However, as discussed further below, preferred oral administration is very difficult with this type of active compound.
Salmon calcitonin, for example, is a peptide hormone which decreases calcium release from bone. When used to treat bone-related diseases and calcium disorders (such as osteoporosis, Paget""s disease, hypercalcemia of malignancy, and the like), it has the effect of helping maintain bone density. Many types of calcitonin have been isolated (human calcitonin, salmon calcitonin, eel calcitonin, elkatonin, porcine calcitonin, and chicken calcitonin). There is significant structural non-homology among the various calcitonin types. For example, there is only 50% percent identity between the amino acids making up human calcitonin and those making up salmon calcitonin. Notwithstanding the difference in molecular structure, salmon calcitonin may be used in the human treatment of the calcitonin-responsive diseases discussed above.
Peptide pharmaceuticals used in the prior art frequently have been administered by injection or by nasal administration. Insulin is one example of a peptide pharmaceutical frequently administered by injection. A more preferred oral administration tends to be problematic because peptide active compounds are very susceptible to degradation in the stomach and intestines. For example, while the prior art has reported an ability to achieve reproducible blood levels of salmon calcitonin when administered orally, these levels are low. This is believed to be because salmon calcitonin lacks sufficient stability in the gastrointestinal tract, and tends to be poorly transported through intestinal walls into the blood. However, injection and nasal administration are significantly less convenient than, and involve more patient discomfort than, oral administration. Often this inconvenience or discomfort results in substantial patient noncompliance with a treatment regimen. Thus, there is a need in the art for more effective and reproducible oral administration of peptide pharmaceuticals like insulin, salmon calcitonin and others discussed in more detail herein.
Proteolytic enzymes of both the stomach and intestines may degrade peptides, rendering them inactive before they can be absorbed into the bloodstream. Any amount of peptide that survives proteolytic degradation by proteases of the stomach (typically having acidic pH optima) is later confronted with proteases of the small intestine and enzymes secreted by the pancreas (typically having neutral to basic pH optima). Specific difficulties arising from the oral administration of a peptide like salmon calcitonin involve the relatively large size of the molecule, and the charge distribution it carries. This may make it more difficult for salmon calcitonin to penetrate the mucus along intestinal walls or to cross the intestinal brush border membrane into the blood.
Normally, the plasma membrane of eukaryotic cells is impermeable to large peptides or proteins. However, certain hydrophobic amino acid sequences, variously called as ferry peptides or membrane translocating sequences, when fused to the N- or C-terminus of functional proteins, can act as membrane translocators, and mediate the transport of these proteins into living cells. This method of protein delivery into cells, while potentially very useful, has two main drawbacks. First, the protein cannot be targeted to any specific cell type. Therefore, once it is injected and enters the circulation, it will presumably enter all cell types in a non-specific, non-receptor mediated manner. This would cause a huge dilution effect, such that very high concentrations of the protein need to be injected in order to achieve an effective concentration in the target cell type. Also, the protein could be extremely toxic when it enters cells in non-target tissues. A third drawback is that the continued presence of the ferry peptide could make the protein very antigenic, and could also interfere with its biological activity. These above drawbacks would apply whether the fusion was delivered by injection or nasal or oral route.
It is accordingly an object of the present invention to provide a therapeutically effective oral pharmaceutical composition for reliably delivering pharmaceutical peptides, e.g., physiologically active peptide agents such as insulin, salmon calcitonin, vasopressin and others discussed herein.
It is a further object of the invention to provide therapeutic methods for enhancing the bioavailability of such peptides.
It is a further object of the invention to provide methods of treating bone-related diseases and calcium disorders by administering salmon calcitonin orally.
In one aspect, the invention provides a pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising:
(A) a therapeutically effective amount of said active peptide linked to a membrane translocator, said membrane translocator is capable of being at least partially cleaved by a blood or lymphatic system protease;
(B) at least one pharmaceutically acceptable pH-lowering agent and/or protease inhibitor; and
(C) an acid resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases.
Preferred peptide active agents include but are not limited to insulin, vasopressin salmon calcitonin, glucagon-like peptide 1, parathyroid hormone, luteinizing hormone releasing hormone, erythropoeitin, and analogs thereof. Especially preferred is salmon calcitonin.
In another aspect, the invention provides a method for enhancing the bioavailability of a therapeutic peptide active agent delivered orally, said method comprising:
(A) linking said peptide agent to a membrane translocator capable of being at least partially cleaved by a plasma protease; and
(B) selectively releasing said peptide active agent linked to said membrane translocator, together with at least one pH-lowering agent and/or protease inhibitor into a patient""s intestine following passage of said peptide active agent, pH-lowering agent and/or protease inhibitor through said patient""s mouth and stomach under protection of an acid resistant protective vehicle which substantially prevents contact between stomach proteases and said peptide agent.
The present invention is believed to reduce the likelihood of proteolytic degradation of the peptide active compound by simultaneously protecting the peptide from proteolytic attack by (1) stomach proteases which are typically most active at acidic pHs and (2) intestinal or pancreatic proteases (which are typically most active at basic to neutral pH).
Then the invention is believed to promote the process by which the peptide crosses the intestinal brush border membrane into the blood due to the presence of the membrane translocator, while continuing to protect the peptide from proteolytic degradation.
An acid resistant protective vehicle protects the peptide active agent from the acid-acting proteases of the stomach. Significant quantities of acid (with which the peptide active agent is intermixed) then reduce the activity of neutral to basic-acting proteases in the intestine (e.g., luminal or digestive protease and proteases of the brush border membrane) by lowering pH below the optimal activity range of these intestinal proteases.
The membrane translocator capable when linked to the active peptide agent enhances transport of the peptide agent through intestinal mucous layers, through the brush border membrane and into the blood. Subsequently, the membrane translocator is cleaved by a blood or lymphatic system protease, thus releasing the active peptide agent in a patient""s system.
Other features and advantages of the present invention will become apparent from the following detailed description of the invention.